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Complement activation in multiple sclerosis plaques: an immunohistochemical analysis.

Ingram G, Loveless S, Howell OW, Hakobyan S, Dancey B, Harris CL, Robertson NP, Neal JW, Morgan BP - Acta Neuropathol Commun (2014)

Bottom Line: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain.This study aims to bring clarity to these questions.We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. morganbp@cardiff.ac.uk.

ABSTRACT

Introduction: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions.

Results: We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.

Conclusions: The findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.

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Related in: MedlinePlus

Quantitative immunolabelling of cells from different tissue areas. Quantitative cellular immunolabelling in different tissue areas from sections of brain and spinal cord tissue from multiple sclerosis (MS; 42 sections from 17 cases with 175 areas examined within the plaque (P), 175 within the peri-plaque (PP), 145 within the white matter (WM) and 195 within the grey matter (GM)), non-neurological controls (C; 14 sections from 7 cases with 70 areas examined from both WM and GM) and neurological controls (NC; 11 sections from 9 cases with 55 areas examined from both WM and GM). Groups show mean values +/_ standard error. Significant results are shown by p value examining differences between the MS group and controls or neurological controls for both WM and GM; differences between the control groups were not included for reasons of clarity. Within the MS group, differences were analysed between P and PP/PP and WM.
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Fig3: Quantitative immunolabelling of cells from different tissue areas. Quantitative cellular immunolabelling in different tissue areas from sections of brain and spinal cord tissue from multiple sclerosis (MS; 42 sections from 17 cases with 175 areas examined within the plaque (P), 175 within the peri-plaque (PP), 145 within the white matter (WM) and 195 within the grey matter (GM)), non-neurological controls (C; 14 sections from 7 cases with 70 areas examined from both WM and GM) and neurological controls (NC; 11 sections from 9 cases with 55 areas examined from both WM and GM). Groups show mean values +/_ standard error. Significant results are shown by p value examining differences between the MS group and controls or neurological controls for both WM and GM; differences between the control groups were not included for reasons of clarity. Within the MS group, differences were analysed between P and PP/PP and WM.

Mentions: All cases examined were from patients with progressive MS, most with long-standing disease (mean disease duration 26 +/- 12 yrs, mean age at death 59 +/- 15 yrs) (Table 1). Both control groups had higher mean age at death (non-neurological controls 76 +/- 13 yrs, p = 0.021; neurological controls 80 +/- 19 yrs, p = 0.003). There were no significant differences between the time to tissue preservation (TTP) in each group (MS 24.88 +/- 21.36 hrs; non-neurological controls 37.57 +/- 40.48 hrs, p = 0.317; neurological controls 40.22 +/- 27.35 hrs, p = 0.190). MS lesions were classified depending on lesion activity. Of the 35 plaques examined, 8 were classified as active and 27 as slowly expanding, 9 of the chronic active and 18 of the chronic inactive type (Figure 1). An additional seven MS sections examined comprised only WM and GM with no plaque. MS sections were almost devoid of lymphocytes or plasma cells with only a few T or B cells identified within the blood vessel wall and perivascular space and an occasional T cell observed within the plaques of active lesions (Additional file 2: Figure S1). CNPase positive oligodendrocytes were universally absent from all plaques examined. In MS WM and GM, astrocyte cell counts were not significantly different from non-neurological or neurological controls (Figures 2 and 3); however microglial cell counts were significantly higher in MS WM than non-neurological control WM, but higher still in the WM and GM of the neurological control group (this being the area of pathology in this group).Figure 2


Complement activation in multiple sclerosis plaques: an immunohistochemical analysis.

Ingram G, Loveless S, Howell OW, Hakobyan S, Dancey B, Harris CL, Robertson NP, Neal JW, Morgan BP - Acta Neuropathol Commun (2014)

Quantitative immunolabelling of cells from different tissue areas. Quantitative cellular immunolabelling in different tissue areas from sections of brain and spinal cord tissue from multiple sclerosis (MS; 42 sections from 17 cases with 175 areas examined within the plaque (P), 175 within the peri-plaque (PP), 145 within the white matter (WM) and 195 within the grey matter (GM)), non-neurological controls (C; 14 sections from 7 cases with 70 areas examined from both WM and GM) and neurological controls (NC; 11 sections from 9 cases with 55 areas examined from both WM and GM). Groups show mean values +/_ standard error. Significant results are shown by p value examining differences between the MS group and controls or neurological controls for both WM and GM; differences between the control groups were not included for reasons of clarity. Within the MS group, differences were analysed between P and PP/PP and WM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4048455&req=5

Fig3: Quantitative immunolabelling of cells from different tissue areas. Quantitative cellular immunolabelling in different tissue areas from sections of brain and spinal cord tissue from multiple sclerosis (MS; 42 sections from 17 cases with 175 areas examined within the plaque (P), 175 within the peri-plaque (PP), 145 within the white matter (WM) and 195 within the grey matter (GM)), non-neurological controls (C; 14 sections from 7 cases with 70 areas examined from both WM and GM) and neurological controls (NC; 11 sections from 9 cases with 55 areas examined from both WM and GM). Groups show mean values +/_ standard error. Significant results are shown by p value examining differences between the MS group and controls or neurological controls for both WM and GM; differences between the control groups were not included for reasons of clarity. Within the MS group, differences were analysed between P and PP/PP and WM.
Mentions: All cases examined were from patients with progressive MS, most with long-standing disease (mean disease duration 26 +/- 12 yrs, mean age at death 59 +/- 15 yrs) (Table 1). Both control groups had higher mean age at death (non-neurological controls 76 +/- 13 yrs, p = 0.021; neurological controls 80 +/- 19 yrs, p = 0.003). There were no significant differences between the time to tissue preservation (TTP) in each group (MS 24.88 +/- 21.36 hrs; non-neurological controls 37.57 +/- 40.48 hrs, p = 0.317; neurological controls 40.22 +/- 27.35 hrs, p = 0.190). MS lesions were classified depending on lesion activity. Of the 35 plaques examined, 8 were classified as active and 27 as slowly expanding, 9 of the chronic active and 18 of the chronic inactive type (Figure 1). An additional seven MS sections examined comprised only WM and GM with no plaque. MS sections were almost devoid of lymphocytes or plasma cells with only a few T or B cells identified within the blood vessel wall and perivascular space and an occasional T cell observed within the plaques of active lesions (Additional file 2: Figure S1). CNPase positive oligodendrocytes were universally absent from all plaques examined. In MS WM and GM, astrocyte cell counts were not significantly different from non-neurological or neurological controls (Figures 2 and 3); however microglial cell counts were significantly higher in MS WM than non-neurological control WM, but higher still in the WM and GM of the neurological control group (this being the area of pathology in this group).Figure 2

Bottom Line: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain.This study aims to bring clarity to these questions.We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. morganbp@cardiff.ac.uk.

ABSTRACT

Introduction: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions.

Results: We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.

Conclusions: The findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.

Show MeSH
Related in: MedlinePlus